title: Isoxazole derivatives as potent transient receptor potential melastatin type 8 (TRPM8) agonists.
abstract: Modulation of the transient receptor potential melastatin type-8 (TRPM8), the receptor for menthol acting as the major sensor for peripheral innocuous cool temperatures, has several important applications in pharmaceutical, food and cosmetic industries. In the present study, we designed 12 isoxazole derivatives and tested their pharmacological properties both in F11 sensory neurons in vitro, and in an in vivo model of cold allodynia. In F11 sensory neurons, single-cell Ca(2+)-imaging experiments revealed that, when compared to menthol, some newly-synthesized compounds were up to 200-fold more potent, though none of them showed an increased efficacy. Some isoxazole derivatives potentiated allodynic responses elicited by acetone when administered to rats subjected to sciatic nerve ligation; when compared to menthol, these compounds were efficacious at earlier (0-2 min) but not later (7-9 or 14-16 min) time points. Docking experiments performed in a human TRPM8 receptor model revealed that newly-synthesized compounds might adopt two possible conformations, thereby allowing to distinguish "menthol-like" compounds (characterized by high efficacy/low potency), and "icillin-like" compounds (with high potency/low efficacy). Collectively, these data provide rationale structure-activity relationships for isoxazole derivatives acting as TRPM8 agonists, and suggest their potential usefulness for cold-evoked analgesia.
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy. Electronic address: ostacolo@unina.it.
authors.forename: Carmine
authors.initials: C
authors.lastname: Ostacolo
authors.forename: Paolo
authors.initials: P
authors.lastname: Ambrosino
authors.forename: Roberto
authors.initials: R
authors.lastname: Russo
authors.forename: Matteo
authors.initials: M
authors.lastname: Lo Monte
authors.forename: Maria Virginia
authors.initials: MV
authors.lastname: Soldovieri
authors.forename: Sonia
authors.initials: S
authors.lastname: Laneri
authors.forename: Antonia
authors.initials: A
authors.lastname: Sacchi
authors.forename: Giulio
authors.initials: G
authors.lastname: Vistoli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Taglialatela
authors.forename: Antonio
authors.initials: A
authors.lastname: Calignano
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009010:Monte Carlo Method; D013329:Structure-Activity Relationship; D050053:TRPM Cation Channels / Q000819:agonists*
chemical_list: D007555:Isoxazoles; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human
keywords: CCI; Ca(2+); Calcium imaging; Chronic constriction injury; DM; DMEM; Dulbecco's modified Eagle's medium; FBS; GM; Isoxazolylamine derivatives; RT; RT-PCR; SAR; Structure–activity relationship; TRPM8 channels; Transient receptor potential melastatin type-8 channels; calcium; chronic constriction injury; differentiation medium; fetal bovine serum; growth medium; reverse-transcription PCR; room temperature; structure–activity relationship; transient receptor potential melastatin type-8 channels